Although human hypertension has a strong genetic component, little is known of its molecular mechanism of genetic basis. A major physiological abnormality in many hypertensive patients and the spontaneously hypertensive rat (SHR) is altered renin-angiotensin responsiveness - accentuated kidney renin secretion and altered adrenal and vascular responsiveness to angiotensin. This may be the result of aberrant expression of the renin gene in renal and extrarenal sites. We propose to characterize renin gene expression both in the kidney and in extrarenal tissues, using genetic and molecular biological techniques. We will look for aberrations in renin gene expression in hypertensive patients and in a rat model of hypertension (SHR). We will study both rat and human hypertension since each has advantages and limitations. In man the presence of restriction fragment length polymorphisms of the renin gene will be compared for genetic linkage with hypertension in large pedigrees and different racial groups. Regulatory and structural mutations of the rat renin gene will be examined and the abnormal regions in the SHR gene will be cloned and sequenced to define the molecular basis of the mutation. The contribution of specific renin alleles to hypertension will be further analyzed by backcrossing studies. In addition to defining renin gene expression in relation to hypertension in vivo we will address specific questions about the renin gene by studying its expression in cultured cells. Five areas will be pursued: 1) Production of human renin protein in quantity; 2) Identification of DNA elements responsible for tissue-specific expression of the gene; 3) Characterization of altered renin precursor expression resulting from alternate promoter and splice site usages; 4) Testing the significance of the renin gene polymorphism by in vitro mutagenesis; 5) Selection and establishment in culture of human cells with sufficient retention of their differentiated phenotype to express correctly the human renin gene at reasonable levels. Areas 2), 3) and 4) will be investigated for rat as well as for human renin genes. These approaches will define at the molecular level the details of renin gene expression in the kidney and in other tissues and will identify potential contributions of renin gene mutations to essential hypertension.